Diagnostic imaging radiopharmaceuticals based on the radioisotope technetium-99m (99mTc) are known for a variety of clinical diagnoses, including functional studies (eg. renal), and perfusion (especially heart and brain). The radioisotope 99mTc has a half-life of 6 hours, hence such 99mTc radiopharmaceuticals are usually prepared from so-called “kits”.
These kits for the preparation of 99mTc radiopharmaceuticals permit the user to maintain stocks of non-radioactive, lyophilised vials containing the necessary reactants, which are designed to be reconstituted with 99mTc-pertechnetate (TcO4−) from a supply of 99mTc to give the desired sterile 99mTc radiopharmaceutical in a facile manner. A sterile solution of 99mTc-pertechnetate in isotonic saline is obtained by elution of a technetium generator with sterile saline as is known in the art.
Kits for the preparation of 99mTc radiopharmaceuticals typically contain:                (i) a ligand which forms a metal complex with 99mTc,        (ii) a biocompatible reducing agent capable of reducing pertechnetate, ie. Tc(VII) to the lower oxidation state of the desired 99mTc metal complex product.        
The biocompatible reducing agent for the 99mTc pertechnetate is typically stannous ion, ie. Sn(II). The kit may contain additional excipients, such as weak chelating agents (such as gluconate, glucoheptonate, tartrate, phosphonate or EDTA); stabilisers; pH-adjusting agents; buffers; solubilisers or bulking agents (such as mannitol, inositol or sodium chloride), to facilitate handling and lyophilisation of the kit components. To facilitate storage and distribution, the non-radioactive kits are usually supplied freeze-dried in a sterile vial with closure. The lyophilised formulation also permits facile reconstitution by the end users with sterile 99mTc-pertechnetate in saline, to give the desired sterile, injectable 99mTc radiopharmaceutical for human use. The shelf life of the non-radioactive technetium kit may be several months.
Radiopharmaceutical compositions may suffer from radiolysis, particularly of the solvent (typically water), with consequent generation of highly reactive free radicals, which may degrade one or more components of the kit composition post-reconstitution. It is known to employ radioprotectants or free radical scavengers to help suppress such degradation. Typically, free radical scavengers are taken from known classes of antioxidant compounds. Ascorbic acid and ascorbates are disclosed to function as stabilisers for stannous-containing non-radioactive kits for the preparation of 99mTc radiopharmaceuticals in U.S. Pat. No. 4,364,920, and have subsequently been widely used in 99mTc radiopharmaceutical preparations. Gentisic acid stabilisers for 99mTc radiopharmaceuticals are disclosed in U.S. Pat. No. 4,233,284. Para-aminobenzoic acid (PABA) and related stabilisers for 99mTc radiopharmaceutical preparations are disclosed in U.S. Pat. No. 4,451,451.
The Myoview™ kit is a 10 ml vial containing the lyophilised formulation:
Tetrofosmin0.23mgStannous chloride dihydrate30μgDisodium sulfosalicylate0.32mgSodium-D-gluconate1.0mgSodium hydrogen carbonate1.8mgpH on reconstitution8.3-9.1,which is sealed under nitrogen gas USP/NF in a 10 ml glass vial, which upon reconstitution with Sterile Sodium (99mTc) Pertechnetate Injection USP/Ph.Eur., yields a solution containing the heart imaging radiopharmaceutical 99mTc-tetrofosmin. Thus, the Myoview™ kit does not contain a radioprotectant.
A ready-to-inject or “conjugate” presentation of Myoview™ has been on sale in Japan since 1997. This “conjugate” form comprises the pre-formed 99mTc-tetrofosmin technetium complex in an aqueous solution in a syringe-vial, ie. a vial with separate plunger and needle, which is designed to be readily assembled to give a syringe containing the radiopharmaceutical. The Myoview™ “conjugate” solution contains ascorbic acid at a concentration of 1.36 mg/ml (7.7 mmolar).
Bastien et al [Nucl. Med. Comm., 20, 480-Abstract 84 (1999)] report that the order of addition of saline and pertechnetate to the Myoview™ kit can influence the radiochemical purity (RCP) of 99mTc-tetrofosmin. Murray et al [Nucl. Med. Comm., 21, 845-849 (2000)] report that the presence of too much nitrogen gas in the headspace of the Myoview™ vial during reconstitution can lead to variable RCP results due to undesirable radiochemical impurities. Murray et al and the Package Instructions of the Myoview™ kit advocate that air is deliberately drawn into the vial during reconstitution to obviate these problems. This is achieved by withdrawing 2 ml of the headspace gas when a vent needle is in place, so that 2 ml of air is drawn into the vial. It is believed that the cause of the problem is reductive autoradiolysis, and that the introduction of oxygen inhibits this degradation.
Patel et al [J. Nucl. Med. Technol., 26(4), 269-273 (1998)] report the results of a study of commercial Myoview™ vials, and conclude that reconstitution with twice the manufacturer's upper limit of radioactivity (up to 18 GBq of 99mTc) is successful, but do not make clear what restrictions were made on the 99mTc-pertechnetate generator eluate used. Such greater radioactivity levels are said to confer benefits of reduced radiation exposure for personnel (one preparation instead of multiple preparations), and reduced variability in QC results. Murray et al (cited above) in fact report that use of radioactive concentrations which exceed those of the Myoview™ Package Instructions lead to poor RCP results.
WO 02/053192 discloses stabilised radiopharmaceutical compositions, which comprise:                (i) a 99mTc metal complex;        (ii) a radioprotectant which comprises ascorbic acid, para-aminobenzoic acid or gentisic acid, or a salt thereof with a biocompatible cation;        (iii) one or more antimicrobial preservatives of formula (I):        
                where R is C1-4 alkyl,        and M is H or a biocompatible cation.        
The Examples of WO 02/053192 include the preparation of stabilised 99mTc-tetrofosmin complex compositions via the addition of radioprotectant and antimicrobial preservative solutions to conventional Myoview™ kits. No specific examples of lyophilised kits containing both tetrofosmin and a radioprotectant are disclosed in WO 02/053192.